There are few documented instances in which human organs are able to respond to injury by complete and perfect replacement of the damaged parts. Under the appropriate conditions the adult digit is one such organ. The digit is composed of a diverse number of distinct cell types making up the various tissues of the digit (e.g. epidermis, nail, nailbed, dermis, adipose, bone, etc.), and in response to amputation, a perfect replica of the tip of the digit including the nail and fingerprint regenerates. Surprisingly little is in fact known about the digit regeneration process in humans, or other mammals, yet the potential for clinical impact seems reasonably high. Using a mouse model we provide evidence that BMP signaling and Msxl function is required for a successful regeneration response in the mouse fetal digit. In this application we propose studies to elucidate the mechanisms by which BMP signaling and Msxl activity regulates fetal digit regeneration. 4 specific aims are proposed. In the first aim we will explore the role of BMP signaling in the in vivo control of fetal digit regeneration by testing the hypothesis that endogenous BMP4 signaling is a regulator of regeneration. In the second aim we will utilize mutations of two type I BMP receptors (Bmpr-IA and Bmpr-IB) in combination with lentivirus mediated expression of constitutively active and dominant negative receptor forms to investigate the mechanism of BMP signaling in digit regeneration. In the third aim we will test the hypothesis that the transcriptional regulator Runx2/Cbfal functions downstream of Msxl and BMP4 in the regeneration response. In the fourth aim we focus on the role that Msxl plays in the formation of a regeneration competent wound epidermis. The long-term goal of this project is to understand the molecular requirements for digit regeneration with the intent of enhancing regenerative capabilities. The results from these studies will impact both clinical and basic sciences.